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RED BLOOD CELLS

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Title: RED BLOOD CELLS


1
RED BLOOD CELLS
  • by
  • Mary Yvonnette C. Nerves, MD, FPSP

2
Erythropoiesis
  • A process by which early erythroid precursor
    cells differentiate to become the mature RBCs
  • Primary regulator ERYTHROPOIETIN
  • - stimulates red cell precursors at all levels
    of maturation to hasten the maturation process
  • - responsible for stimulating the premature
    release of reticulocytes into the bloodstream.

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Erythropoiesis
  • Total erythropoiesis
  • - total number of red blood cells (RBCs)
  • - measured by the myeloid-erythroid (ME)
    ratio from aspirate smears plus the estimate
    of cellularity from biopsy sections

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  • Effective erythropoiesis
  • - number of viable and functional RBCs
    available for physiologic needs
  • - reflects the balance between the number
    of cells produced and their life span
  • - measured by the reticulocyte count, which is
    normally 1 of the total RBC count

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Stages of Maturation
  1. Pronormoblast (Rubriblast)
  2. Basophilic Normoblast (Prorubriblast)
  3. Polychromatophilic Normoblast (Rubricyte)
  4. Orthochromatic Normoblast (Metarubricyte)
  5. Reticulocyte
  6. Erythrocyte

9
Pronormoblast
  • Earliest recognizable and largest cell of
    the erythrocyte series
  • Morphology
  • - Size 12 20 um
  • - Nucleus large round, oval, dark violet
    fine chromatin 1 2 nucleoli
  • - Cytoplasm deep blue spotty, basophilic
    w/ a perinuclear halo
  • - N/C Ratio 81
  • - BM () 1

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Basophilic Normoblast
  • Hemoglobin synthesis begins at this stage
  • Morphology
  • - Size 10 15 um
  • - Nucleus large round to sl oval
    condensed, coarse chromatin 0 1 nucleoli
  • - Cytoplasm deeply basophilic clusters of
    free ribosomes
  • - N/C Ratio 61
  • - BM () 1-4

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Polychromatic Normoblast
  • Increased production of hemoglobin pigmentation
    and decreasing amounts of RNA
  • Last stage in which the cell is capable of
    mitoses
  • Morphology
  • - Size 10 - 15 um
  • - Nucleus round nucleus, deep staining, may
    be centrally or eccentrically located
    coarse clumped chromatin
  • - Nucleoli 0

14
  • Morphology
  • - Cytoplasm abundant blue-gray (RNA) to
    pink-gray (hemoglobin)
  • - N/C Ratio 41
  • - BM () 10-20

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Orthochromatic Normoblast
  • The last nucleated stage
  • Cannot synthesize DNA and cannot undergo
    cellular division
  • The NRBC sometimes seen in the
    peripheral circulation

17
  • Morphology
  • - Size 8 - 10 um
  • - Nucleus small pyknotic nucleus dense
    chromatin 0 nucleoli
  • - Cytoplasm abundant red-orange
    cytoplasm uniform in color
  • - N/C Ratio 12
  • - BM () 5-10

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Reticulocyte
  • Slightly larger than the mature RBC with
    residual amts of RNA
  • Reticulocyte count an index of bone marrow
    activity or effective erythropoiesi
  • Morphology
  • - Size 8 - 10 um
  • - Nucleus anucleate cell containing small
    amt of basophilic reticulum (RNA)
  • - Nucleoli 0
  • - Cytoplasm large amt of blue-pink
    staining hemoglobin cytoplasm

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Erythrocyte
  • A biconcave 6 8 um disc
  • Life span 120 days
  • Main function to transport hemoglobin,
    a protein that delivers oxygen from the lungs to
    tissues and cells
  • Contains 90 hemoglobin and 10 H2O
  • normal conc of RBCs varies w/ age, sex
    geographic distribution

23
  • Morphology
  • - Size 7 - 8 um
  • - Nucleus anucleated cell
  • - Nucleoli 0
  • - Cytoplasm pink staining, zone of
    central pallor is 1/3 of cell diameter
    devoid of hemoglobin
  • - N/C Ratio NA

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Hemoglobin Structure Function
  • A conjugated protein that serves as the vehicle
    for the transportation of O2 and CO2
  • When fully saturated, each gram of Hgb can hold
    1.34 mL of O2
  • A molecule of Hgb consists of 2 pairs of
    polypeptide chains (globin) and 4
    prosthetic heme grps each contg 1 atom of ferrous
    iron

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DESCRIPTION of TERMS
  • SIZE DESCRIPTORS
  • Anisocytosis variation in the sizeof the RBCs
    due to a pathologic condition

31
  • Normocytic normal sized biconcave disc RBC
  • - normal MCV

32
  • Microcytic Smaller RBCs less than 6 um
  • - MCV lt 80 fl
  • - Defect / Change abn size due to failure
    of hgb synthesis
  • - Dse IDA, Thalassemia, Chronic dse
  • Macrocytic Larger RBCs greater than 9um
  • - MCV gt 90 fl
  • - Defect / Change impaired DNA synthesis /
    stress erythropoiesis
  • - Dse Megaloblastic anemia / liver dse /
    MDS / Alcoholism / Malaria

33
Macrocytic
Microcytic
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  • CHROMICITY DESCRIPTORS
  • Normochromic normal in color pale central
    area occupies less than 1/3
  • - Defect / Change normal amt of Hgb
  • - Normal indices
  • Hypochromic an RBC that has a decreased Hgb
    complement
  • - central pallor exceeds 1/3 of diameter
    of cell
  • - Defect / Change reduced Hgb content
    ( MCHC)
  • - Assoc conditions IDA / Thalassemia

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  • Hyperchromic no central pallor
  • - Defect / Change greater than normal
    MCHC
  • - Assoc condition Spherocytosis

Hyperchromic
Hypochromic
38
  • Polychromasia blue-gray coloration
  • - Defect / Change presence of RNA
  • - Assoc condition increased erythropoietic
    activity / hemorrhage / hemolysis

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  • SHAPE DESCRIPTORS
  • Poikilocytosis variation in shape of the RBC
  • - Defect / Change irreversible alteration
    of membrane
  • - Assoc conditions Anemia / Hemolytic
    states

41
  • Discocyte normal biconcave erythrocyte - 6 8
    um diameter 0 2 um thickness
  • - Aka Normocyte

Normal Red Cells (SEM)
42
  • Acanthocyte spheroid w/ 3 12 irreg
    spikes or spicules
  • - Aka spur cell
  • - decreased cell volume
  • - Defect / Change inc ratio of chole to
    lecithin
  • - Assoc conditions
  • end-stage liver dse
  • Pyruvate kinase def
  • Hemolytic anemia
  • Abetalipoproteinemia

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  • Blister cell contains 1 or more vacuoles
  • - Aka Bite cells
  • - thinned periphery
  • - Defect / Change formed by removal of
    Heinz bodies
  • - Assoc conditions
  • Hemolytic episodes
  • G6PD def
  • Hemoglobinopathies

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  • Codocyte peripheral rim of Hgb surr by
    clear area central hemoglobinized area
    (bulls eye)
  • - Aka target cell
  • - Defect / Change excess of surface to
    volume ratio
  • - Assoc conditions
  • Hemoglobinopathies
  • Thalassemia
  • Liver dse
  • Postsplenectomy

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  • Dacryocyte teardrop or pear-shaped w/ single
    elongated point or tail
  • - Aka tear drop cell
  • - Defect / Change squeezing fragmentation
    during splenic passage
  • - Assoc conditions
  • Myeloid metaplasia
  • Thalassemia
  • Megaloblastic anemia
  • Hypersplenism

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  • Drepanocyte crescent-shaped cell that lacks
    zone of central pallor
  • - Aka Sickle cell
  • - Defect / Change polymerization
    of deoxygenated Hgb
  • - Assoc conditions
  • Sickle cell anemia
  • SC disease
  • S-thalassemia

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  • Echinocyte regular 10-30 scalloped
    short projections evenly distributed / spiny-like
  • - Aka Burr cell / crenated RBC
  • - Defect / Change Depletion of ATP
  • Exposure to hypertonic soln
  • Artifact in air drying
  • - Assoc conditions
  • Uremia
  • Cirrhosis / Hepatitis
  • Chronic renal dse

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  • Ovalocyte egglike or oval-shaped cell
  • - Defect / Change
  • Hgb has bipolar arrangement
  • Reduction in membrane chole
  • - Assoc conditions
  • Megaloblastic BM
  • Myelodysplasia
  • Sickle cell anemia

55
  • Elliptocyte rod or cigar shape,
    generally narrower than ovalocytes
  • - Defect / Change polarization of Hgb
  • - Assoc conditions
  • Thalassemia
  • Iron def
  • Hereditary elliptocytosis

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  • Schistocyte Fragmented RBCs varying in
    size shape
  • - Aka Helmet cells
  • - Defect / Change extreme fragmentation produc
    ed by damage of RBC by fibrin, altered vessel
    walls, prosthetic heart valves
  • - Assoc conditions
  • DIC / TTP / Burns
  • Microangiopathic hemolytic anemia

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  • Spherocyte smaller in diameter than normal
    RBC w/ concentrated Hgb content no visible
    central pallor
  • - Defect / Change
  • lowest surface area to volume ratio
  • defect of loss of membrane
  • - Assoc conditions
  • Hereditary spherocytosis
  • Iso- autoimmune hemolytic anemia
  • Severe burns
  • Hemoglobinopathies

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  • Stomatocyte normal sized cell w/ slitlike
    area in center
  • - Defect / Change
  • artifact of slow drying
  • known to have inc permeability to Na
  • - Assoc conditions
  • Hereditary stomatocytosis
  • Acute alcoholism
  • Liver dse

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RED CELL INCLUSIONS
  • Basophilic Stippling
  • - cytoplasmic remnants of RNA
  • - Fine thin round dark blue granules
    uniformly distributed
  • - Defect/Change represents polychromasia
    (reticulocyte)
  • - Coarse medium sized uniformly
    distributed
  • - Defect/Change represents impaired
    erythropoiesis

64
  • Basophilic Stippling
  • - Assoc conditions
  • Thalassemia
  • Lead Poisoning
  • Increased reticulocytosis

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  • Cabot Ring
  • - rings, loops, or figure eights red to purple
  • - Defect / Change remnants of
    microtubules of mitotic spindle
  • - Assoc conditions
  • Megaloblastic anemia
  • Dyserythropoiesis

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  • Heinz bodies
  • - deep purple irregularly shaped
    inclusions found on RBC inner surface of
    membrane
  • - Defect / Change represent precipitated,
    denatured Hgb due to oxidative injury
  • - Assoc conditions
  • Hereditary defects in HMS
  • G6PD def
  • Unstable Hgbs
  • Splenectomized pts
  • Thalassemia

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  • Howell-Jolly bodies coarse round
    densely stained purple 1-2 um granules
    eccentrically located on periphery of membrane
  • - Defect / Change nuclear remnants
    contain DNA
  • - Assoc conditions
  • Megaloblastic anemia
  • Severe hemolytic process
  • Thalassemia
  • Accelerated erythropoiesis

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  • Pappenheimer bodies small, 2-3 um irregular
    basophilic inclusions that aggregate in small
    clusters near periphery w/ Wrights stain
  • - Defect / Change unused iron (nonheme)
    deposits
  • - Assoc conditions
  • Sideroblastic anemia
  • Defective erythropoiesis
  • MDS
  • Hemolytic anemia
  • Thalassemia

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  • Ringed Sideroblasts
  • - Nucleated RBC that contains nonheme
    iron particles (siderotic granules) arranged in
    ring form
  • - Defect / Change excessive iron overload in
    mitochondria of normoblasts
  • - due to defective heme synthesis
  • - Assoc conditions
  • Sideroblastic anemia
  • MDS

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Ringed Sideroblasts Prussian blue iron stain
showing excess accumulation of iron as ferritin
in mitochondria ringing nucleus.
77
  • Siderocyte non-nucleated cell containing
    iron granules
  • - Defect / Change excessive iron overload in
    mitochondria of normoblasts
  • - due to defective heme synthesis
  • - Assoc conditions
  • Sideroblastic anemia
  • MDS

78
  • Autoagglutination clumping of RBCs
  • - Defect / Change presence of antibody
  • - Assoc conditions
  • Cold agglutinin
  • AHA

79
  • Rouleaux Formation alignment of RBCs linear
    appearing as stacks of coins
  • - Defect / Change concentration of
    fibrinogen immunoglobulin
  • - Assoc conditions
  • MM / Waldenstroms macroglobulinemia

80
Red Cell Studies
81
  • Hematologic tests used to measure several
    important parameters that reflect rbc structure
    and function
  • 1) Hemoglobin determination
  • 2) Erythrocyte count
  • 3) Hematocrit
  • 4) Erythrocyte Indices MCH, MCHC, MCV
  • 5) Reticulocyte Count
  • 6) Osmotic Fragility Test
  • 7) Erythrocyte Sedimentation Rate (ESR)

82
Adult Reference Ranges for Red Blood Cells
Measurement (units) Men Women Women
Hemoglobin (gm/dL) 13.6-17.2 12.0-15.0 12.0-15.0
Hematocrit () 39-49 33-43 33-43
Red cell count (106/µL) 4.3-5.9 3.5-5.0 3.5-5.0
Reticulocyte count () 0.5-1.5 0.5-1.5 0.5-1.5
Mean cell volume (µm3) 82-96 82-96 82-96
Mean corpuscular hemoglobin (pg) 27-33 27-33 27-33
Mean corpuscular hemoglobin concentration (gm/dL) 33-37 33-37 33-37
RBC distribution width 11.5-14.5 11.5-14.5 11.5-14.5

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  • Hemoglobin
  • - involves lysing the erythrocytes, thus
    producing an evenly distributed solution of
    hemoglobin in the sample
  • - Hemiglobincyanide Mtd blood is diluted in
    a soln of K3Fe(CN6). The K3Fe(CN6) oxidizes Hgbs
    to hemiglobin (metHgb) and K cyanide provides
    cyanide ions to form HiCN, w/c has a broad
    absorption max at a wl of 540 nm

85
  • Erythrocyte Count
  • - involves counting the number of rbcs per
    unit volume of whole blood.
  • - expressed as number of cells per unit
    volume, specifically cells/µL
  • - NV Female 4.2 - 5.4 x 106/µL
  • Males 4.7 - 6.1 x  106/µL

86
  • Hematocrit
  • - sometimes referred to as the Packed
    Cell Volume (PCV) or volume of packed red cells
  • - is the ratio of the volume of RBCs to that of
    the whole blood
  • - varies with age and sex
  • - expressed as a percentage or as a decimal
    fraction

Plasma
Buffy coat
Red cells
87
  • Erythrocyte Indices
  • 1) Mean Cell Volume (MCV)
  • - average volume of red cells
  • - calculated from the Hct and RBC count
  • MCV Hct x 1000
  • RBC (in millions/uL)
  • - expressed in femtoliters (fl) or cubic
    micrometers

88
2) Mean Cell Hemoglobin (MCH) - content
(weight) of Hgb of the average red cell -
calculated from the Hgb and RBC count MCH
Hgb (in g/L) RBC (/L) - value
is expressed in picograms (pg)
89
  • 3) Mean Cell Hemoglobin Concentration (MCHC)
  • - the average conc of Hgb in a given volume of
    packed red cells
  • - calculated from the Hgb conc the Hct
  • MCHC Hgb (in g/dL)
  • Hct
  • - expressed in g/dL

90
Morphologic Classification of Anemias Morphologic Classification of Anemias Morphologic Classification of Anemias
Type of Anemia Blood Constants Blood Constants
Type of Anemia MCV (mm3 or fl) MCHC (g.Hb/dl.RBC or mmol/l)
Microcytic hypochromic 60-87 20-30
Macrocytic normochromic 103-160 32-36
Normocytic normochromic 87-103 32-36
Microcytic normochromic 60-87 32-36
91
  • Reticulocyte Count
  • - Principle Reticulocytes are immature
    non- nucleated red cells that contain RNA
    and continue to synthesize Hgb after the loss
    of the nucleus
  • - Supravital staining blood is briefly
    incubated in a soln of new MB or BCB, the RNA
    is precipitated as a dye-ribonucleoprotein compl
    ex ? dark blue network (reticulum or
    filamentous strand)
  • - NV 0.5 1.5 or 24 84 x 109/L

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  • Osmotic Fragility Test (OFT)
  • - a measure of the ability of red cells to take
    up fluid without lysing
  • - Red cells are suspended in a series of tubes
    contg hypotonic solns of NaCl solns varying
    from 0.9 to 0.0, incubated at room temp for
    30 mins and centrifuged
  • - the percent hemolysis in the supernatant solns
    is measured plotted for each NaCl conc.

94
  • - The larger the amount of red cell
    membrane (surface area) in relation to the size
    of the cell, the more fluid the cell is capable
    of absorbing before rupturing
  • - Cells that are more spherical, w/ a decreased
    surface/volume ratio, have a limited capacity
    to expand in hypotonic solns lyse at a higher
    conc of NaCl than do normal biconcave cells ?
    OFT

95
  • - Cells that are hypochromic flatter have a
    greater capacity to expand in hypotonic solns,
    lyse at a lower conc than do normal cells, are
    said to have decreased osmotic fragility
  • - Cells with increased surface/volume ratio are
    osmotic resistant ? IDA, thalassemia, liver dse,
    reticulocytosis

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  • Erythrocyte Sedimentation Rate (ESR)
  • - detect and monitor an inflammatory response
    to tissue injury (an acute phase response) in
    which there is a change in the plasma conc of
    several proteins
  • - Principle When well-mixed venous blood is
    placed in a vertical tube, RBCs will tend to
    fall toward the bottom. The length of the fall
    of the top of the column of RBCs in a given
    interval of time is called the ESR

98
  • - ESR is affected by (3) FACTORS
  • a) erythrocytes
  • b) plasma composition
  • c) mechanical / technical factors
  • - Red Cell Factors
  • Anemia increases ESR (change in RBC plasma
    ratio favors rouleaux fotn)
  • ESR is directly proportional to the weight of
    the cell aggregate inversely proportional to
    the surface area
  • Microcytes sediment slower than macrocytes
  • Rouleaux accelerate the ESR
  • Red cells w/an abnormal or irregular shape
    hinder rouleaux fotn lower the ESR

99
  • - Plasma Factors
  • Elevated levels of fibrinogen accelerate ESR
  • Albumin lecithin retard ESR
  • Cholesterol accelerate ESR
  • - Mechanical / Technical Factors
  • A tilt of 3o can cause errors up to 30 ? ESR
  • ESR increases as the temp increases
  • ESR tubes with a narrower than standard
    bore will generally yield lower ESR
  • ESR stands fro gt 60 mins ? falsely elevated ESR
  • Greater conc of EDTA ? falsely low ESR
  • - Methods Westergren Mtd / Wintrobe Mtd

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ERYTHROCYTE DISORDERS
102
  • Two main disorders affecting RBCs
  • 1. Polycythemia (Erythrocytosis)
  • - an elevated Hct level above the normal
    range
  • 2. Anemia
  • - a reduction below normal limits of the
    total circulating red cell mass

103
Pathophysiologic Classification of Polycythemia
Relative Reduced plasma volume (hemoconcentration)
Absolute Absolute
Primary Polycythemia vera, rare erythropoietin receptor mutations (low erythropoietin)
Secondary High erythropoietin
  Appropriate lung disease, high-altitude living, cyanotic heart disease
  Inappropriate erythropoietin-secreting tumors (e.g., renal cell carcinoma, hepatocellular carcinoma, cerebellar hemangioblastoma)
104
POLYCYTHEMIA
  • May be classified into (2) major conditions
  • 1) Relative Polycythemia
  • - an increase in the Hct or red cell count as
    a result of decreased plasma volume
  • - total red cell mass is NOT increased
  • - Assoc conditions acute dehydration or
    hemoconcentration / pts on diuretic therapy /
    Gaisbocks syndrome (psedopolycythemia or
    stress erythrocytosis)
  • - BM Normal

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  • 2) Absolute (or Secondary) Polycythemia
  • - an erythropoietin mediated increase in RBCs
    and Hgb due primarily to a hypoxic situation
  • - increase in the total red cell mass in the
    body assoc w/ normal or sl increased plasma
    volume
  • - Assoc conditions tumors / anabolic
    steroids / renal dso such as cystic dse,
    hydronephrosis / adrenal cortical
    hyperplasia
  • - BM Erythroid hyperplasia

106
3) Polycythemia rubra vera (Primary
Erythrocytosis) - an absolute increase in all
cell types, RBCs, WBCs and platelets - not
dependent on erythropoietin levels - BM all
three cell lines increased (panhyperplasia)
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ANEMIA
  • Decreased oxygen carrying capacity of the blood
  • Anemia may also be "defined" in terms of the Hb
    content
  • Hb lt 12 g/dL in an adult male
  • Hb lt 11 g/dL in an adult female

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  • ANEMIAS SECONDARY TO BLOOD LOSS
  • Acute e.g., hemorrhage due to trauma,
    massive GI bleeding, or child delivery. Usually
    the iron stores remain normal.
  • Chronic e.g., bleeding peptic ulcer or
    excessive menstrual bleeding.

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HYPOPROLIFERATIVE ANEMIAS (Impaired Production)
  • reduced production of red cells can be subdivided
    into
  • deficiency of haematinics
  • iron deficiency
  • B12 and folate deficiency
  • dyserythropoiesis (production of defective cells)
  • anaemia of chronic disorders (AOCD)
  • myelodysplasia
  • sideroblastic anaemia
  • marrow infiltration (myelophthisic anemia)
  • aplasia (failure of production of cells)
  • aplastic anaemia
  • red cell aplasia

114
Iron Deficiency Anemia
  • Normal forms of iron (Fe) and iron metabolism
  • Functional iron is found in Hb, myoglobin, and
    enzymes (catalase cytochromes)
  • Ferritin physiological storage form
  • Hemosiderin degraded ferritin lysosomal debris
    (Prussian blue positive)
  • Iron is transported by transferrin

115
  • causes
  • Dietary deficiency elderly, children and poor
  • Increased demand children pregnant women
  • Decreased absoprtion
  • generalized malabsorption
  • after gastrectomy
  • Chronic blood loss
  • GI bleeding (e.g. peptic ulceration, carcinoma
    of stomach or colon)
  • menorrhagia
  • urinary tract bleeding
  • Hook worm (Ancylostoma duodenale adult worm
    sucks 0.2 ml blood/day)

116
  • Lab Findings
  • Microcytic, hypochromic anemia. Low serum iron
  • BM show absence of iron
  • Ferritin Low serum ferritin indicates low body
    stores of iron
  • Transferrin These carrier proteins will be
    unsaturated and available to bind iron, hence the
    Total Iron Binding Capacity (TIBC) is increased
    with anemia.

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Anemia of Chronic Disease (AOCD)
  • Char by iron being trapped in BM macrophages
  • Can be grouped in 3 categories
  • - chronic microbial infections (eg.
    Osteomyelitis)
  • - chronic immune disorders (eg. RA)
  • - Neoplasms (eg. lymphoma, breast/lung CA)
  • Chronic inflamm dso ?inc IL-1, TNF, IF-Gamma ?
  • - reduction in renal erythropoietin ? marrow
    erythroid precursors do notproliferate
  • - hepcidin synthesis in liver ?inhibits release
    of iron

122
  • Labs low serum iron
  • increased serum ferritin
  • decreased TIBC
  • normochromic, normocytic anemia or
    hypochromic, microcytic anemia

123
Megaloblastic Anemia
  • A group of dso in which the blood and BM
    hematopoietic cells display changes
  • Pathogenesis impaired DNA synthesis (delayed
    mitoses) while RNA is not impaired this produces
    nuclear-cytoplasmic asynchrony
  • Megaloblastic anemias can be divided into groups
  • - anemia caused by B12 deficiency
  • - anemia caused by folate deficiency
  • - anemias nonresponsive to either therapy

124
  • important background knowledge
  • B12
  • vitamin B12 is required for DNA replication and
    inhibition of transcription of DNA to RNA
  • B12 is normally absorbed from gut by the
    following mechanism
  • secretion of intrinsic factor by parietal cells
    in stomach
  • binding of intrinsic factor and vitamin B12 in
    lumen
  • intrinsic factor- B12 complex is absorbed in
    terminal ileum through pinocytotic vesicles
  • Folate
  • folate is required for DNA replication and
    inhibition of transcription of DNA to RNA
  • lack of B12 or folate means that RNA builds up
    and the cells become too large

125
  • Causes
  • causes of vitamin B12 deficiency (pernicious
    anaemia)
  • lack of intrinsic factor
  • atrophic gastritis - parietal cells are destroyed
  • gastrectomy
  • malabsorption of B12 not related to lack of
    intrinsic factor
  • tropical sprue or bacterial overgrowth of
    terminal ileum
  • ileal disease (e.g. Crohn's disease affecting the
    terminal ileum)
  • fish tape-worm (these attach to intestinal wall,
    and therefore in large enough numbers, may
    prevent B12-intrinsic factor complex absorption
    in terminal ileum)
  • poor diet - rare

126
  • causes of folate deficiency
  • poor diet - especially in alcoholics
  • malabsorption - coeliac disease
  • increased cell turnover (e.g. leukaemia, chronic
    haemolysis, pregnancy)
  • antifolate drugs (e.g. phenytoin)

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  • Peripheral Blood Findings

WBCs Normal or decreased
RBCs Decreased
Hgb Decreased
MCV Increased (usualy gt 100 fl)
MCH Increased
MCHC Normalor slightly decreased
Platelet count Normal or decreased
Reticulocyte count Decreased
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  • Morphologic Abnormalities
  • Large RBC's with nuclear-cytoplasmic dyssynchrony
  • Ovalocytes The large RBC's tend to have an
    oval-shape.

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  • Hypersegmented Neutrophils One of the earliest
    signs of disease. 5 or 6 lobes
  • Howell-Jolly Bodies Nuclear fragments seen in
    Megaloblastic anemia.

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Aplastic Anemia
  • pancytopenia associated w/ a severe reduction in
    the amt of hematopoietic tissue that results in
    deficient production of blood cells
  • Etiology
  • Acquired
  • idiopathic
  • Chemical agents
  • Physical agents
  • Viral infections
  • Inherited
  • Fanconis anemia

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  • Pure red cell aplasia erythrocyte stem cells are
    suppressed, but the other formed elements of
    blood are unaffected
  • Anemia due to isolated depletion of erythroid
    precursors in the marrow, and may be acute or
    chronic.
  • Lab Findings
  • - Normochromic, normocytic or macrocytic anemia
  • - Reticulocytes are decreased or absent because
    it is hypoproliferative.
  • - BM hypocellular or dry tap
  • reduction in all cell lines

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HEMOLYTIC ANEMIAS (Increased Destruction)
  • Grp of dso that can be inherited, acquired,or
    drug-induced
  • Char by an increased red cell destruction or
    shortened survival of the RBC
  • Char by increased BM activity, polychromasia,
    nucleated RBCs and an increased reticulocyte
    count w/ stress reticulocytes

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  • Hemolytic anemias share the ff. features
  • 1. shortened red cell life span, that is,
    premature destruction of red cells
  • 2. elevated erythropoietin levels and
    increased erythropoiesis in the marrow other
    sites
  • 3. accumulation of products of Hgb
    catabolism, due to an increased rate of red
    cell destruction

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  • HEMOLYTIC ANEMIAS
  • Acquired
  • Immune-mediated
  • - Autoimmune
  • - Alloimmune (Transfusion)
  • - Drug-induced
  • Microangiopathic
  • Infection
  • Hereditary
  • Enzymopathies
  • Membranopathies
  • Hemoglobinopathies

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  • INTRINSIC DEFECTS
  • Hereditary Spherocytosis
  • abnormal cell membrane assoc cytoskeleton causing
    red cells to be spherical and fragile
  • principle defect is an abnormality of the
    membrane protein ankyrin
  • Lab findings Normocytic, hyperchromic anemia
    (normal MCV and increased MCHC)
  • - increased pigment catabolism, erythroid
    hyperplasia, reticulocytosis
  • - red cells with increased OFT

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  • Glucose-6-Phosphate Dehydrogenase Deficiency
  • Normal G6PD metabolises glucose, and
    forms small amounts of ATP (which maintains
    the cell cytoskeleton and membrane) and NADPH
    (which mops up free radicals)
  • G6PD def renders the cell susceptible to
    damage by free radicals
  • an X-linked recessive condition, in which
    haemolytic crises are precipitated by
    infections or certain drugs
  • Lab findings poikilocytes spherocytes,
    Heinz bodies (stain w/ methyl violet)

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  • HEMOGLOBINOPATHIES
  • Normal Hgb
  • HbA / HbF / HbA2 (adult)
  • Hb Gower-1 and 2 / Hb-Portland (embryonic)

Hemoglobin-A alpha2, beta2 Predominant hemoglobin in adults
Hemoglobin-A2 alpha2, delta2 Found in normal adults
Hemoglobin-F alpha2, gamma2 Fetal (cord) hemoglobin, with higher O2-binding affinity
Hemoglobin-S alpha2, beta2 (beta Glu-6 ---gt Val) Sickle-Cell Hemoglobin. Sickle crisis can result from low O2-tension.
Hemoglobin-C alpha2, beta2 (beta Glu-6 ---gt Lys) Hemoglobin-C Disease. Second most common hemoglobinopathy.
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  • THALASSEMIA
  • Caused by impaired production of one of the
    polypeptide chains of the Hb molecule
  • Epidemiology Mediterranean, African Asian
    ancestry
  • autosomal recessive disease
  • Types according to clinical severity
  • thalassaemia major homozygote
  • thalassaemia minor heterozygote
  • Types according to molecular defect
  • beta thalassaemia
  • alpha thalassaemia

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  • Beta-Thalassemia
  • Major (Homozygous state)
  • - severe hypochromic, microcytic anaemia,
    hepato- splenomegaly, marrow hyperplasia causing
    skeletal deformities, haemochromatosis develops
    with repeated transfusions
  • Minor (Heterozygous states)
  • - reduction in HbA, but increase in HbA2 mild
    anaemia with hypochromia

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Clinical Nomenclature Genotype Disease Disease Molecular Genetics Molecular Genetics
ß-Thalassemias ß-Thalassemias ß-Thalassemias ß-Thalassemias ß-Thalassemias ß-Thalassemias
Thalassemia major Homozygous ß0-thalassemia (ß0/ß0) Homozygous ß0-thalassemia (ß0/ß0) Severe requires blood transfusions Severe requires blood transfusions Rare gene deletions in ß0/ß0 Defects in transcription, processing, or translation of ß-globin mRNA
  Homozygous ß-thalassemia (ß/ß) Homozygous ß-thalassemia (ß/ß)     Rare gene deletions in ß0/ß0 Defects in transcription, processing, or translation of ß-globin mRNA
Thalassemia intermedia ß0/ß ß/ß ß0/ß ß/ß Severe, but does not require regular blood transfusions Severe, but does not require regular blood transfusions Rare gene deletions in ß0/ß0 Defects in transcription, processing, or translation of ß-globin mRNA
Thalassemia minor ß0/ß ß/ß ß0/ß ß/ß Asymptomatic with mild or absent anemia red cell abnormalities seen Asymptomatic with mild or absent anemia red cell abnormalities seen Rare gene deletions in ß0/ß0 Defects in transcription, processing, or translation of ß-globin mRNA
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  • Alpha-Thalassemia
  • note that there are 4 copies of the alpha globin
    gene (not 2), and therefore four possible degrees
    of alpha thalassaemia exist
  • 3 good copies - silent carrier
  • 2 good copies - mild anaemia with microcytosis
  • 1 good copy - moderate haemolytic anaemia with
    hypochromia and mycrocytosis HbH (tetramer of
    beta)
  • 0 good copies - lethal in utero (hydrops fetalis)

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a-Thalassemias a-Thalassemias a-Thalassemias a-Thalassemias
Hydrops fetails -/--/- Lethal in utero without transfusions Mainly gene deletions
HbH disease -/--/a Severe resembles ß-thalassemia intermedia Mainly gene deletions
a-Thalassemia trait -/-a/a (Asian) -/a-/a (black African) Asymptomatic, like ß-thalassemia minor Mainly gene deletions
Silent carrier -/aa/a Asymptomatic no red cell abnormality Mainly gene deletions
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Thalassemia Major Patient with thalassemia major
due to heterozygous hemoglobin E/B thalassemia.
Note prominent target cells, anisopoikilocytosis,
and three nucleated red cells (normoblasts)  
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  • Sickle Cell Disease
  • Endemic to Sub-saharan Africa, due to
    heterozygous advantage conferred against
    Falciparum Malaria (infected RBC's preferentially
    sickle and are thus taken to the spleen and
    sequestered, limiting the spread of infection)
  • PATHOGENESIS Point-mutation of Glu ? Val at 6th
    position of beta-globin chain
  • Pathophysio abn Hgb polymerises at low O2
    saturation causing abnormal rigidity and
    deformity of red cells and become abnormality
    fragile (and undergo haemolysis and sludge in
    small vessels)
  • autosomal recessive, with a point mutation in
    beta gene forming an abnormal HbS more common
    in Negroes

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  • Lab. Findings
  • Smear normochromic, normocytic anemia,
    increased polychromasia, normoblasts are present,
    numerous target cells, Howell-Jolly and
    Pappenheimer bodies are present, sickle cells
  • OFT decreased
  • BM normoblastic hyperplasia w/ increased iron
    storage
  • Electrophoresis no HbA, 80 HbS (SCD)

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Sickle Cells (SEM) Scanning electron micrograph
(SEM) showing sickle cells obstructing small
vessel.  
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  • EXTRINSIC DEFECTS
  • Immune Hemolytic Anemias
  • Dso in w/c erythrocyte survival is reduced
    because of the deposition of Ig /or
    complement on the red cell membrane
  • Classification
  • 1. Autoimmune Hemolytic Anemia
  • 2. Isoimmune Hemolytic Anemia
  • 3. Drug-induced Hemolytic Anemia
  • LAB () direct indirect antiglobulin tests

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Agglutination of erythrocytes is seen on this
peripheral blood smear
Coombs Test
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  • Traumatic Hemolytic Anemia
  • Char by striking morphologic abn of the red
    cells, w/c include fragments (schistocytes)
    irregularly contracted cells (triangular cells,
    helmet cells)
  • MICROANGIOPATHIC HEMOLYSIS RBC's being damaged
    by intravascular fibrin-clots, in small vessels.
    DIC, TTP, HUS.
  • MACROANGIOPATHIC HEMOLYSIS Damage by artifical
    heart valves.

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